Most forms of cancer are derived from solid tumors (Shockley et al., Ann. N.Y. Acad. Sci. 1991, 617: 367–382), which have proven resistant in the clinic to therapies such as the use of monoclonal antibodies and immunotoxins. Anti-angiogenic therapy for the treatment of cancer developed from the recognition that solid tumors require angiogenesis (i.e., new blood vessel formation) for sustained growth (Folkman, Ann. Surg. 1972, 175: 409–416; Folkman, Mol. Med. 1995, 1(2): 120–122; Folkman, Breast Cancer Res. Treat. 1995, 36(2): 109–118; Hanahan et al., Cell 1996, 86(3): 353–364). Efficacy of anti-angiogenic therapy in animal models has been demonstrated (Millauer et al., Cancer Res. 1996, 56:1615–1620; Borgstrom et al., Prostrate 1998, 35:1–10; Benjamin et al., J. Clin. Invest. 1999, 103: 159–165; Merajver et al., Proceedings of Special AACR Conference on Angiogenesis and Cancer 1998, Abstract #B-11, January 22–24) in the art. In the absence of angiogenesis, internal cell layers of solid tumors are inadequately nourished. Further, angiogenesis (i.e., aberrant vascularization) has now also been shown to be required for the growth of non-solid, hematological tumors and has been implicated in numerous other diseases (e.g., ocular neovascular disease, macular degeneration, rheumatoid arthritis, etc.).
Contrastingly, normal tissue does not require angiogenesis except under specialized circumstances (e.g., wound repair, proliferation of the internal lining of the uterus during the menstrual cycle, etc.). Accordingly, a requirement for angiogenesis is a significant difference between tumor cells and normal tissue. Importantly, the dependency of tumor cells on angiogenesis, when compared to normal cells, is quantitatively greater than differences in cell replication and cell death between normal tissue and tumor tissue, which are often exploited in cancer therapy.
Tumor angiogenesis can be initiated by cytokines such as vascular endothelial growth factor and/or fibroblast growth factor, which bind to specific receptors on endothelial cells in the local vasculature under hypoxic conditions. The activated endothelial cells secrete enzymes which remodel the associated tissue matrix and modulate expression of adhesion molecules such as integrins. Following matrix degradation, endothelial cells proliferate and migrate toward the tumor, which results in the generation and maturation of new blood vessels.
Interestingly, protein fragments, such as endostatin, kringle 5 and PEX, which inhibit angiogenesis, are produced by degradation of matrix proteins (O'Reilly et al., Cell 1997, 88:277–285; O'Reilly et al., Cell, 994, 79:315–328; Brooks et al., Cell, 1998, 92:391–400). Accordingly, these protein fragments may inhibit new angiogenesis, thus preventing tumor growth and metastasis.
However, protein fragments have significant drawbacks associated with their use (i.e., are difficult and expensive to produce in large quantities, poor pharmacological properties, susceptible to degradation, etc.). One approach has been to identify small peptide fragments of these larger proteins, which still retain a significant portion of the anti-angiogenic activity of the parent protein.
Although the search for peptides that inhibit angiogenesis has provided compounds with significant effectiveness in preventing growth of new blood vessels, molecules with superior activity profiles are still needed. Accordingly, novel peptides are needed to fully explore the potential of peptides in preventing angiogenesis. The novel peptides may have longer plasma half-lives, more resistance to degradation, increased bio-availability, higher affinity, greater selectivity, etc. in comparison to peptides described in the art (Livant, U.S. Pat. No. 6,001,965; Livant, U.S. Pat. No. 6,472,369). Such novel peptides may be effective in treating various diseases associated with angiogenesis such as cell migration, cell invasion and cell proliferation.